Extended-infusion Piperacillin-tazobactam Research Articles

Impact of extended-infusion piperacillin-tazobactam in a Canadian community hospital

BackgroundStudies have demonstrated improved clinical outcomes with extended infusion (EI) piperacillin/tazobactam (TZP) compared to standard infusion (SI). However, there is less evidence on its benefits in noncritically-ill patients. Hospital-wide EI TZP was implemented at our site on February 21, 2012. Our objectives were to compare clinical, safety and economic outcomes between EI and SI TZP. MethodsA retrospective cohort study of all adult patients who received EI TZP (3.375 g IV q8h infused over 4 hours and SI TZP for ≥ 48 hours during 3 years pre-and postimplementation was conducted. The primary study outcome was 14-day mortality while secondary outcomes included length of hospital stay (LOS), nursing plus pharmacy cost, occurrence of Clostridioides difficile infection, readmission within 30 days and change in Pseudomonas aeruginosa minimum inhibitory concentration (MIC) distribution for TZP. The primary outcome and binary secondary outcomes were analyzed using a logistic regression model. LOS was examined using time to event analysis. Cost was examined using linear regression modelling. ResultsOverall, 2034 patients received EI TZP and 1364 patients received SI TZP. EI TZP was associated with lower odds of mortality (OR 0.76, 95% CI 0.63–0.91), lower odds of C. difficile infection (OR 0.59, 95% CI 0.41–0.84) and 8% lower cost (estimate 0.92, 95% CI 0.87–0.98) compared to SI TZP. ConclusionsHospital-wide implementation of EI TZP was associated with lower odds of 14-day mortality and incidence of C. difficile infection with cost savings at our institution.

730. Cefiderocol for the Treatment of Achromobacter xylosoxidans Infections in Two Lung Transplant Patients with Cystic Fibrosis

Background Achromobacter xylosoxidansis a highly resistant Gram-negative bacterium that causes chronic infections in patients with cystic fibrosis (CF). Treatment options for A. xylosoxidans are limited. In the peri-lung transplant setting, the treatment of A. xylosoxidans infections is especially challenging. Cefiderocol is a novel siderophore cephalosporin antibiotic with broad anti-Gram-negative activity, including against A. xylosoxidans. We report here two cases of compassionate use of cefiderocol in CF lung transplant recipients with A. xylosoxidans infection.MethodsCefiderocol was obtained through compassionate use from its manufacturer, with approval from the local Institutional Review Board. In the first case, it was used as salvage treatment, and in the second case as a planned part of the peri-transplant regimen.ResultsA male in his 20s with CF and a trimethoprim-sulfamethoxazole (TMP-SMX) allergy was chronically colonized by A. xylosoxidans, which was sensitive only to piperacillin–tazobactam (PIP-TAZ), and TMP-SMX. After lung transplant, he developed A. xylosoxidansbacteremia, and extended-infusion PIP-TAZ was started. Repeat bronchoscopy grew A. xylosoxidans. Due to lack of improvement, cefiderocol was added to PIP-TAZ with rapid clinical improvement. However, after completing his course, he was readmitted with A. xylosoxidans pneumonia. He was treated with 6 weeks of cefiderocol and imipenem and has been well since with an 8-month follow-up. In the second case, cefiderocol was used as part of the planned peri-transplant regimen for a female with CF in her late teens, with chronic A. xylosoxidans colonization, which was intermediate to PIP-TAZ, and resistant to all other drugs tested. Her native lungs grew 4+ A. xylosoxidans at the time of explant. Post-transplant, she was treated with 5 weeks of meropenem and 6 weeks of cefiderocol. At four-month follow-up, she is doing well. However, she is asymptomatically colonized with A. xylosoxidanspost-transplant. Isolates from both cases were susceptible to cefiderocol (case #1 MIC = 0.12; case #2 pretreatment MIC = 1, post-treatment MIC.ConclusionCefiderocol may be a useful option for lung transplant recipients with A. xylosoxidans infections.DisclosuresAnne Lachiewicz, MD, MPH, MicroGenDx: Consultant; Shionogi: Consultant.

Association Between Estimated Pharmacokinetic/Pharmacodynamic Predictions of Efficacy and Observed Clinical Outcomes in Obese and Nonobese Patients With Enterobacteriaceae Bloodstream Infections

BackgroundEvidence on pharmacokinetic/pharmacodynamic (PK/PD) alterations and clinical outcomes in obese patients with serious infections remains limited. This study aimed to evaluate predicted PK/PD indices of efficacy and observed clinical outcomes between obese and nonobese patients receiving cefepime or piperacillin-tazobactam for Enterobacteriaceae bacteremia.MethodsThis was a retrospective study of adult inpatients from 1/2012 to 9/2015 with Enterobacteriaceae bacteremia who received empiric cefepime or piperacillin-tazobactam. The primary outcome was clinical cure. First-dose free-drug exposure was estimated via predicted concentrations generated from population PK analyses and used to assess PD target attainment (>50% fT > minimum inhibitory concentration [MIC]) for the specific Enterobacteriaceae isolate. Multivariable logistic regression was utilized to identify independent predictors of clinical cure.ResultsOne hundred forty-two patients were included, 57 obese and 85 nonobese. Clinical cure was achieved in 68.4% of obese and 62.4% of nonobese patients (P = .458). No significant difference in outcomes was observed when evaluated by World Health Organization (WHO) obesity classes. The PK/PD target was achieved in 98.2% of obese and 91.8% of nonobese patients (P = .144). Independent predictors of clinical cure were immunosuppression and a shorter duration of bacteremia. Obesity was not identified as a significant predictor of clinical outcomes.ConclusionsNeither predicted PK/PD parameters nor clinical outcomes differed significantly between obese and nonobese patients treated with piperacillin-tazobactam or cefepime. As the majority of patients received extended-infusion piperacillin-tazobactam for bacteremia due to pathogens with low MICs, the potentially detrimental pathophysiologic derangements caused by obesity may not have been realized. Further studies are warranted to establish the optimal treatment of serious infections in obese patients.

Safety of Extended Infusion Piperacillin-Tazobactam plus Vancomycin versus Standard Infusion Piperacillin-Tazobactam plus Vancomycin in General Medicine Patients with a diagnosis of Healthcare associated Pneumonia

Objective: The primary safety objective is Acute Kidney Injury (AKI), defined as an increase in serum creatinine of at least 0.5 mg/dL or a 50% increase in serum creatinine from baseline at any time during antibiotic therapy. The objective of this study is to assess safety of Extended Infusion Piperacillin-tazobactam (EIPT) and vancomycin therapy versus Standard Infusion Piperacillin-tazobactam (SIPT) and vancomycin in general medicine patients, and to evaluate if one treatment modality predisposes patients to a greater risk of nephrotoxicity. Setting: Data from a large academic medical center was analyzed over a 3 month period pre and post implementation of extended infusion piperacillin-tazobactam protocol. Design: A retrospective analysis was conducted comparing patients admitted to the hospital with a diagnosis of Healthcare Associated Pneumonia (HCAP) who received EIPT plus vancomycin versus SIPT plus vancomycin. Patients: Adult hospitalized patients on combination therapy with two or more Serum Creatinine (SCr) measurements were included. Patients were excluded if they are less than 18 years of age, are pregnant, or if they are on any form of dialysis including continuous renal replacement therapy. Conclusion: A total of 241 patients were evaluated for AKI. Safety outcomes were compared between the two treatment groups and contributing factors for developing AKI were also assessed. The incidence of AKI was significantly higher in the SIPT and vancomycin group (20.0%) compared with the EIPT and vancomycin group (10.0%) in the analysis (p=0.033). There were no significant differences in the baseline characteristics between the groups with the exception of a higher percentage of patients with a diagnosis of hypertension in the EIPT and vancomycin group (p<0.05).

Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship.

Despite their common use as an empirical combination therapy for the better part of a decade, there has been a recent association between combination therapy with vancomycin and piperacillin-tazobactam and high rates of acute kidney injury (AKI). The reasons for this increased association are unclear, and this analysis was designed to investigate the association. Retrospective cohort and case-control studies were performed. The primary objective was to assess if there is an association between extended-infusion piperacillin-tazobactam in combination with vancomycin and development of AKI. The secondary objectives were to identify risk factors for AKI in patients on the combination, regardless of infusion strategy, and to evaluate the impact of AKI on clinical outcomes. AKI occurred in 105/320 (33%) patients from the cohort receiving combination therapy with vancomycin and piperacillin-tazobactam, with similar rates seen in those receiving intermittent (53/160 [33.1%]) and extended infusions (52/160 [32.5%]) of piperacillin-tazobactam. Independent risk factors for AKI in the cohort included having a documented Gram-positive infection, the presence of sepsis, receipt of a vancomycin loading dose (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.05 to 4.71), and receipt of any concomitant nephrotoxin (OR, 2.44; 95% CI, 1.41 to 4.22). For at-risk patients remaining on combination therapy, the highest rates of AKI occurred on days 4 (10.7%) and 5 (19.3%). The incidence of AKI in patients on combination therapy with vancomycin and piperacillin-tazobactam is high, occurring in 33% of patients. Receipt of piperacillin-tazobactam as an extended infusion did not increase this risk. Modifiable risk factors for AKI include receipt of a vancomycin loading dose, concomitant nephrotoxins, and longer durations of therapy.

Comparison of Acute Kidney Injury in Patients Receiving Vancomycin Plus Traditional Versus Extended-Infusion Piperacillin-Tazobactam in a VA Medical Center

Comparison of Acute Kidney Injury in Patients Receiving Vancomycin Plus Traditional Versus Extended-Infusion Piperacillin-Tazobactam in a VA Medical Center

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children.

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m(2), respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

Using Higher Doses to Compensate for Tubing Residuals in Extended-Infusion Piperacillin-Tazobactam

To mathematically assess drug losses due to infusion line residuals and evaluate methods to compensate for drug loss due to residual volumes in intravenous pump tubing. Literature was accessed through Ovid MEDLINE (1996-February 2013), using combinations of the search terms tubing residuals, residual volume, residual medication, intravenous infusions, intravenous injections, piperacillin, piperacillin-tazobactam, β-lactams, equipment design, infusion pumps, extended infusion, extended administration, and prolonged infusion. In addition, select reference citations from publications identified were reviewed. All articles that involved extended-infusion piperacillin-tazobactam implementation strategies were included in the review. Infusion pump characteristics and tubing residuals can affect extended-infusion piperacillin-tazobactam dosing strategies. Two studies addressing tubing residuals were identified. Both studies recommended increasing infusion volumes to compensate for tubing residuals. One study also recommended decreasing infusion-line dead space by using alternative infusion pump systems. Study calculations suggest that higher doses of piperacillin-tazobactam may be used to account for medication left in tubing residuals if alternative infusion pump systems cannot be obtained, and increased infusion volumes are not an option. Extended-infusion piperacillin-tazobactam has been used as a method of maximizing pharmacodynamic target attainment. Use of higher doses of piperacillin-tazobactam may be a reasonable method to compensate for drug loss due to residual volumes in large-bore intravenous pump tubing.

System-Wide Implementation of the Use of an Extended-Infusion Piperacillin/Tazobactam Dosing Strategy: Feasibility of Utilization From a Children's Hospital Perspective

BackgroundUse of extended infusions of piperacillin/tazobactam (PT) in adult patients has been described, but data in children are limited. ObjectiveThe goal of this study was to determine the feasibility of using an extended-infusion PT dosing strategy as the standard of care in a children's hospital. MethodsThis was a prospective observational study of patients aged >30 days who received PT after admission to a freestanding, tertiary care children's hospital. After institution of an extended-infusion PT dosing protocol as the standard dosing option, patients receiving PT were prospectively assessed for presence of and reasons for changes in dosing regimen. ResultsA total of 332 patients, with a median age of 5 years (interquartile range, 1.9–12 years) and median weight of 19.9 kg (interquartile range, 11.7 – 37.6 kg) received PT (100 mg/kg based on piperacillin component). Extended-infusion PT was used for the duration of PT therapy in 92% (n = 304) of patients. Twenty-eight patients (8%) received a traditional infusion over 30 minutes, with 19 of 28 being changed from extended infusion and 9 of 28 being empirically prescribed traditional infusion PT. The most commonly encountered reason for not using extended infusions was coadministration of vancomycin (17 of 28 [61%]) and lack of compatibility data with PT. Dosing errors, which were voluntarily reported, were infrequent (1.8% [n = 6]). The few observed dosing errors were likely attributable to the overall ordering process at our institution, which requires ordering as the milligram per kilogram dose as total PT rather than based on piperacillin component as is commonly documented in pediatric dosing references. ConclusionsResults of this study suggest that extended-infusion PT dosing was feasible in this specific children's hospital. Ninety-two percent of patients received our institution's preferred dosing regimen; a small percentage of patients still needed to receive traditional infusion times.

The Retrospective Cohort of Extended‐Infusion Piperacillin‐Tazobactam (RECEIPT) Study: A Multicenter Study

To compare the effectiveness of extended-infusion piperacillin-tazobactam with that of similar-spectrum, nonextended-infusion [H9252]-lactam antibiotics in the treatment of gram-negative infections. Multicenter, retrospective medical record review. Fourteen hospitals throughout the United States. A total of 359 adults treated for gram-negative infections between January 1, 2007, and February 28, 2010, with either 4-hour extended-infusion piperacillin-tazobactam (186 patients) or nonextended-infusion comparator antibiotics (173 patients), which consisted of cefepime, ceftazidime, imipenem-cilastatin, meropenem, doripenem, or piperacillin-tazobactam. Deidentified data were collected on demographics, renal function, Acute Physiology and Chronic Health Evaluation II score, chronic health conditions, source of infection and type of organism, intensive care unit (ICU) length of stay, total length of stay, type and duration of antimicrobial therapy, and in-hospital mortality. The primary outcome was mortality rate of the patients receiving extended-infusion piperacillin-tazobactam versus those receiving nonextended-infusion comparator antibiotics. Secondary outcomes were hospital length of stay, ICU length of stay, and total duration of antibiotic therapy. Baseline characteristics were similar between groups, except a significantly lower proportion of patients in the extended-infusion group were treated with a concomitant intravenous aminoglycoside (5.9% vs 16.2%, p<0.01), were infected with Pseudomonas species (22.6% vs 39.9%, p<0.01), or had positive respiratory cultures (30.7% vs 43.4%, p=0.01). Antibiotic duration, hospital length of stay, and ICU length of stay were similar between groups. In-hospital mortality was significantly decreased in the extended-infusion piperacillin-tazobactam group versus those receiving comparator antibiotics (9.7% vs 17.9%, p=0.02). Multivariate analysis confirmed that extended-infusion piperacillin-tazobactam prolonged survival by 2.77 days (p<0.01) and reduced the risk of mortality (odds ratio 0.43, p=0.05). Pharmacodynamic dosing using extended-infusion piperacillintazobactam demonstrated favorable outcomes, including mortality, when compared with nonextended-infusion, similar-spectrum [H9252]-lactams in the treatment of patients with documented gram-negative infections. Prospective, randomized trials are needed to further corroborate these findings.

Implementation of an extended-infusion piperacillin–tazobactam program at an urban teaching hospital

The development and implementation of an extended-infusion piperacillin-tazobactam program at an urban teaching hospital are described. A multidisciplinary team was formed to address the feasibility of converting from the standard 30-minute infusion to an extended infusion of piperacillin- tazobactam. Before hospitalwide implementation, feasibility studies were performed in a subset of patients to identify potential barriers to program implementation. On the day of hospitalwide conversion, the orderables for piperacillin-tazobactam were reprogrammed in the computerized prescriber-order-entry system to allow separate options for the 30-minute infusion (for pediatric patients) and the extended-infusion regimen. After selecting the orderable for the extended-infusion regimen, an electronic message appeared to remind prescribers of the rationale for this change and recommended indications for piperacillin-tazobactam. Program success was prospectively evaluated on 11 weekdays after hospitalwide conversion for all 96 adult inpatients receiving piperacillin-tazobactam. Of the 194 piperacillin-tazobactam doses observed, 90% were appropriate, with compliance increasing to 100% by the end of the observation period. There was near-complete cessation of the every-6-hour dosage interval and a marked increase in the every-8-hour and every-12-hour dosage intervals. The number of piperacillin-tazobactam doses per 1000 patient-days significantly decreased during the postimplementation period. During the postimplementation period, pharmacy expenditures related to piperacillin-tazobactam decreased by 18% and the total number of grams of piperacillin-tazobactam purchased decreased by 24%. A hospitalwide program for the administration of extended-infusion piperacillin-tazobactam was safely and successfully implemented using a multi-disciplinary approach in an urban teaching hospital.

Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients.

This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CL(CR)) on overall clearance, TZP clearance was made proportional to the estimated CL(CR). A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CL(CR). The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CL(CR). In contrast, the PTA for the extended-infusion TZP regimen exceeded >or=80% for MIC values of <or=8 mg/liter across all CL(CR) strata. All regimens were associated with suboptimal PTA for MIC values of >or=32 mg/liter irrespective of the CL(CR). The CL(CR) adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CL(CR) of <or=20 ml/min.

Outcomes of extended infusion piperacillin/tazobactam for documented Gram-negative infections

This comparison of intermittent versus extended-infusion piperacillin–tazobactam among patients with Gram-negative infections revealed similar mortality and length of stay. Outcomes remained similar when stratified by MIC value.